PROJECT SUMMARY/ABSTRACT Among those who are hospitalized as a result of traumatic injury, ~27-41% develop posttraumatic stress disorder (PTSD), while the remaining ~59-73% are considered resilient. Despite heterogeneity in PTSD outcomes, mediating variables that confer risk for the disorder have been difficult to identify. Results from prior research suggest that the endocannabinoid signaling system (ECSS) buffers the stress response. Pharmacologically blocking the ECSS increases anxiety-like behaviors in rodents after a stressor; in healthy adults, ECSS activates after a social stressor. In contrast, there is a growing consensus that the ECSS is dysfunctional in those with PTSD. Cross-sectional studies demonstrate deficient activation of the ECSS in those with PTSD, while preliminary research from the study team shows that abnormally elevated ECSS predicts PTSD up to 6 months. Divergent direction of effects suggest the presence of yet unknown factors that shape whether ECSS will lead to stress buffering following a traumatic event. To better understand the role of ECSS in acute and long-term PTSD, the current study proposes to investigate dysfunction of the ECSS in relation to neural functioning, particularly as ECSS receptors are densely located in brain regions responsible for the expression and regulation of fear. Abnormal fear regulation is prevalent in PTSD and qualified by aberrant engagement of these regions demonstrated by functional magnetic resonance imaging (fMRI) studies. The ability of the ECSS to protect against PTSD may therefore be disrupted in the context of abnormal neural excitability driven by fear dysregulation. The proposed Ruth L. Kirschstein National Research Service Award (NRSA) was designed to examine whether fear extinction neurocircuitry measured by fMRI moderates the relationship between the ECSS and acute PTSD 2-weeks post-injury (Aim I) and chronic PTSD 12-months post-injury (Aim II). In addition, whether fear extinction neurocircuitry moderates the relationship between ECSS and differential PTSD trajectories over 12 months using latent growth mixture modeling (LGMM) will be tested, as prior findings are mainly taken from cross-sectional studies that ignore variations in symptom course. Training goals of this fellowship are to further develop the applicant's knowledge and research skills specific to fear extinction, the ECSS, acute traumatic injury, and longitudinal study design. To our knowledge, this project is the first to examine the relationship between ECSS markers and brain activation during fear regulation as prospective predictors of PTSD in trauma-exposed individuals. Results from this project may ultimately lead to a greater understanding of the neurobiological mechanisms underlying the involvement of endocannabinoids as a buffer against the development of psychological sequelae.